Anionic phospholipids, principally phosphatidylserine, become exposed on the external surface of viable vascular endothelial cells in tumors, providing an excellent marker for tumor vascular targeting. We recently raised an IgG monoclonal antibody, 3G4, which binds to anionic phospholipids in a B2-glycoprotein I-dependent manner. It inhibited tumor growth in a variety of rodent tumor models by stimulating antibody-dependent cellular cytotoxicity toward tumor vessels. In the present study, we tested the hypothesis that docetaxel, which is known to have antivascular effects on tumors, might induce exposure of anionic phospholipids on tumor vasculature and, thus, enhance the antitumor activity of 3G4. Treatment of human umbilical vascular endothelial cells with subtoxic concentrations of docetaxel (20 pmol/L) in vitro caused anionic phospholipids to be externalized without inducing apoptosis. Docetaxel treatment of mice increased the percentage of tumor vessels that expose anionic phospholipids from 35% to 60%. No induction of phosphatidylserine was observed on vessels in normal tissues even after systemic treatment with docetaxel. Treatment of mice bearing orthotopic MDA-MB-435 human breast tumors with 3G4 plus docetaxel inhibited tumor growth by 93%. Treatment of mice bearing disseminated MDA-MB-435 tumors with 3G4 plus docetaxel reduced the average number of tumor colonies in the lungs by 93% and half the animals did not develop tumors. In both tumor models, the antitumor effect of the combination was statistically superior (P < 0.01) to that of docetaxel or 3G4 alone. Combination therapy reduced the tumor vessel density and plasma volume in tumors to a greater extent than did the individual drugs. The combination therapy was no more toxic to the mice than was docetaxel alone. These results indicate that, as an adjuvant therapy, 3G4 could enhance the therapeutic efficacy of docetaxel in breast cancer patients. (Cancer Res 2005; 65(10): 4408-16)
We have generated and characterized a rat mAb (E6) that reacts specifically with both human and mouse PSMA and have demonstrated that an immunotoxin constructed from E6 is safe and effective against human prostatic carcinoma cells growing subcutaneously in nude mice.
Aims-To examine the relation between the replication error (RER) phenotype and other genetic events, clinical features, and long term survival in patients with Dukes' B stage II (T3,N0,M0) colorectal cancer. Methods-RER phenotype was investigated in 159 patients by PCR amplification of microsatellite marker loci on chromosomes 5q, 17p, 17q, and 18q from tumour DNA extracted from archival tissue. Data on activating c-Ki-ras mutations were available from a previous study. Immunohistochemical detection of p53 and c-erbB-2 expression was performed on paraYn wax embedded tissue. Results-Of 159 colorectal cancers studied, 22 (14%) were RER+ while 137 (86%) were RER− for two or more loci. RER+ tumours were more commonly located in the right colon, tended to be larger than RER− tumours, and were more often poorly diVerentiated than RER− cancers. No significant associations were seen between RER status and the presence of a mutant c-Ki-ras gene, or between RER status and p53, c-erbB-2, or c-myc gene expression. Univariate survival analysis showed that outcome was similar in RER+ and RER− cases. Multivariate survival analysis showed that the relative risk of death for patients with RER+ cancers was 0.95 that of patients with RER− cancers. Conclusions-The results suggest that, while the RER phenotype may be associated with some diVerences in tumour pathology (site, size, diVerentiation), it is not associated with the genetic alterations studied or with significant diVerences in long term survival.
Aims-To compare differences in cell proliferation indexes and apoptotic indexes between cutaneous basal and squamous cell carcinomas, in an attempt to suggest an explanation for the differences in their biological behaviour. Methods-Forty cases of cutaneous basal cell carcinoma (BCC) and 40 cases of moderately and well differentiated squamous cell carcinoma (SCC) were retrieved from the archives. Sections, 4 gm thick, were cut from formalin fixed, paraffin wax embedded tissue in each case and stained with haematoxylin and eosin. These were then examined for mitotic and apoptotic figures per 1000 cells. Sections from the same cases were also immunostained with the mouse monoclonal antibody Ki67 (MIBI); positive nuclear staining was counted per 1000 cells. Results-No significant differences were found between the mitotic indexes and apoptotic indexes in these tumours. There was, however, a significant difference in Ki67 (MIBI) staining, with greater staining in the squamous cell carcinomas. Conclusion-Estimation of the mitotic and apoptotic indexes did not reveal any differences between these two tumour types. The proliferation indexes, assessed by Ki67 immunostaining, did differ. This may be one of the factors underlying the more aggressive behaviour of SCC. ( Clin Pathol 1996;49:549-551) Keywords: skin, neoplasm, proliferation.
Department of
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